The annual morbidity and mortality associated with influenza virus, and its capacity to undergo genetic variation leading to highly virulent strains capable of causing worldwide pandemics, makes this virus both an ongoing and emerging threat to public health. There is therefore a high priority need for the development of an animal model that closely mimics human disease, and which can be used to gain a better understanding of influenza virus pathogenesis and the viral factors associated with highly virulent and pandemic strains. In this application, we propose to develop a pig-tailed macaque (Macaca nemestrina) model of influenza virus infection. These animals will be infected with wild-type A/Texas/96/31 virus (a mildly pathogenic strain often used in vaccine production) or with engineered strains of A/Texas/96/31 that contain one or more genes from the highly virulent 1918 pandemic strain (commonly referred to as the Spanish Flu). We will closely monitor clinical, pathological, and cytopathic changes in these animals and will correlate these findings with global gene expression data obtained using macaque oligonucleotide microarrays. These studies will be performed by Dr. Carole Baskin (DVM), who has recently completed a 4-year fellowship in the Department of Comparative Medicine, and who is seeking the training necessary to develop an independent research program focused on using nonhuman primates as models of human infectious disease. She will be mentored in these studies by Dr. Michael G. Katze, Professor of Microbiology and Associate Director at the Washington National Primate Research Center. The training environment provides outstanding facilities, expertise in nonhuman primate models of virus infection, and state-of-the-art resources for using genomic technologies and bioinformatics to study virus-host interactions. There are also ample opportunities for scientific interactions with influenza experts across the country, including a number of renowned scientists working on the 1918 virus. These studies will provide training in the skills needed to use nonhuman primates as models for human infectious disease, to develop and implement a scientifically sound research program, and to incorporate genomic technologies for the evaluation of gene expression as well as clinical data. The findings generated by these studies will provide new insights into how influenza virus causes human disease and why certain strains of the virus have a markedly increased capacity to do so. Such knowledge may lead to new therapeutic or vaccine strategies, which may serve as vital countermeasures against future influenza outbreaks. [unreadable] [unreadable] [unreadable]